Raf kinase is a key component of the RAS→Raf→MEK→ERK/MAP kinase signaling pathway, which plays a fundamental role in the regulation of cell growth, division and proliferation, and, when constitutively activated, causes tumorigenesis (19). Among several isoforms of Raf kinase, the B-type, or BRAF, is the strongest activator of the downstream MAP kinase signaling (25). The BRAF gene is located on Chromosome 7.
The RAF proteins are highly conserved serine/threonine protein kinases that have an important role in cell proliferation, differentiation, and programmed cell death (1). The RAF proteins activate mitogen-activated protein kinase kinase (MEK), which in turn activates the mitogen-activated protein kinase (MAPK) pathway (2). Inappropriate and/or continuous activation of this pathway provides a potent promitogenic force resulting in abnormal proliferation and differentiation in many human cancers (3). Davies et al. (4) reported that BRAF is frequently mutated in a variety of human tumors, especially in malignant melanoma and colon carcinoma. The most common reported mutation was a missense thymine (T)→adenine (A) transversion at nucleotide 1796 (T1796A; amino acid change in the BRAF protein is Val599→Glu599) observed in 80% of the malignant melanoma tumors. Functional analysis revealed that this transversion was the only detected mutation that caused constitutive activation of BRAF kinase activity, independent of RAS activation, by converting BRAF into a dominant transforming protein (4).
Papillary thyroid cancer (PTC) is the most common thyroid cancer, accounting for about 80% of thyroid malignancies (20). Although PTC is usually indolent and curable with surgical thyroidectomy followed by radioiodine treatment, many patients do have recurrence and some become incurable and die (18); (15); (17); (24). Consequently, it is important to undertake appropriate risk stratification and prognostic evaluation for patients with PTC in order to provide optimal clinical management of the cancer. This is usually achieved based on evaluation of various clinicopathologic risk factors, such as the age and gender of the patient, the size of the tumor, and extrathyroidal invasion and metastasis status (18); (15); (17); (24). With the demonstration of the oncogenic effect of the BRAF T1796A transversion mutation (4), it is conceivable that BRAF mutation plays an important tumorigenic role in PTC and may thus affect the clinicopathologic outcomes of these cancers. Indeed, it has recently been shown that BRAF mutation was associated with a higher prevalence of extrathyroidal invasion and advanced pathologic stage of PTC (27). In another recent analysis on PTC, however, no significant association of the BRAF mutation with extrathyroidal invasion was demonstrated although a marginally significant association of the BRAF mutation with advanced pathologic stage was observed (26). There is a need in the art for improved and/or additional means for detecting, diagnosing, categorizing, treating, and predicting outcomes for thyroid cancers.